In the past two decades Alzheimer's disease (AD) has been recognized as a dominant cause of dementia and death in aged populations. The most characteristic findings include neocortical and hippocampal neuropathology, with beta-amyloid-containing neuritic plaques, neurofibrillary tangles, synapse loss, gliosis, and severe brain and cortical atrophy, all of which may be exacerbated by oxidative stress. Transgenic murine models have since been developed which mimic some of the neuropathological findings in AD. The major goals of Specific Aim 1 in this project are to use the double transgenic murine model co-expressing mutant amyloid precursor protein (APP) and mutant presenilin 1 (PS1) to characterize age- and gender-related alterations in neuronal pathways, particularly the noradrenergic projections from the pontine brainstem. Specifically, we will quantify the level of beta-amyloid (amyload) and the extent to which dtg APP/PS1 mice exhibit: neuronal degeneration in the locus coeruleus (LC) and noradrenergic terminals in the amygdala and hippocampus; microgliosis and astrocytosis in LC and projection fields. Specific Aim 2 will assess the ability of 17-beta estradiol (E2) to provide neuroprotection against this AD-type neuropathology. These studies will be performed in middle-aged ovariectomized mice. We hypothesize that chronic E2 treatment will reduce the amyload and other neurodegenerative indices. We will use state-of-the-art neurostereological techniques to assess the effects of aging, gender, and E2 on AD-type neuropathology in discrete brain regions of dtg APP/PS1 mice. The results will confirm the noradrenergic pathophysiology in the model of AD-like amyloid deposition, and establish a basis for the development of new strategies for the therapeutic management of AD.